U.S. patent application number 11/203901 was filed with the patent office on 2006-08-03 for therapeutic agent for overactive bladder resulting from cerebral infarction.
This patent application is currently assigned to EISAI CO., LTD.. Invention is credited to Masaharu Nakai, Osamu Yokoyama.
Application Number | 20060172992 11/203901 |
Document ID | / |
Family ID | 36757408 |
Filed Date | 2006-08-03 |
United States Patent
Application |
20060172992 |
Kind Code |
A1 |
Yokoyama; Osamu ; et
al. |
August 3, 2006 |
Therapeutic agent for overactive bladder resulting from cerebral
infarction
Abstract
An agent for treating overactive bladder resulting from cerebral
infarction, comprising administrating a compound having a
cholinesterase inhibitory activity or a pharmacologically
acceptable salt thereof.
Inventors: |
Yokoyama; Osamu; (Fukui,
JP) ; Nakai; Masaharu; (Fukui, JP) |
Correspondence
Address: |
DICKSTEIN SHAPIRO MORIN & OSHINSKY LLP
1177 AVENUE OF THE AMERICAS (6TH AVENUE)
41 ST FL.
NEW YORK
NY
10036-2714
US
|
Assignee: |
EISAI CO., LTD.
Tokyo
JP
|
Family ID: |
36757408 |
Appl. No.: |
11/203901 |
Filed: |
August 15, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60601425 |
Aug 13, 2004 |
|
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|
Current U.S.
Class: |
514/214.01 ;
514/297; 514/319; 514/411 |
Current CPC
Class: |
A61K 31/473 20130101;
A61K 31/55 20130101; A61K 31/407 20130101; A61K 31/445
20130101 |
Class at
Publication: |
514/214.01 ;
514/319; 514/297; 514/411 |
International
Class: |
A61K 31/55 20060101
A61K031/55; A61K 31/445 20060101 A61K031/445; A61K 31/473 20060101
A61K031/473; A61K 31/407 20060101 A61K031/407 |
Claims
1. A method for treating overactive bladder resulting from cerebral
infarction, comprising administering a compound having a
cholinesterase inhibitory activity, a pharmacologically acceptable
salt or a solvate thereof to a patient with the overactive bladder
resulting from cerebral infarction.
2. A method according to claim 1, wherein the compound having a
cholinesterase inhibitory activity is a cyclic amine derivative
represented by the following general formula: ##STR83## (wherein, J
is: (a) a substituted or unsubstituted (1) phenyl group, (2)
pyridyl group, (3) pyradyl group, (4) quinolyl group, (5)
cyclohexyl group, (6) quinoxalyl group or (7) furyl group; (b) a
monovalent or divalent group derived from a group selected from the
group consisting of (1) indanyl, (2) indanonyl, (3) indenyl, (4)
indenonyl, (5) indandionyl, (6) tetralonyl, (7) benzsuberonyl, (8)
indanolyl, and (9) a group represented by formula ##STR84## in all
of which a phenyl group may be substituted; (c) a monovalent group
derived from a cyclic amide compound; (d) a lower alkyl group; or
(e) a group represented by formula R.sup.1--CH.dbd.CH-- (wherein
R.sup.1 is a hydrogen atom or a lower alkoxycarbonyl group), B is a
group represented by formula ##STR85## a group represented by
formula ##STR86## a group represented by formula ##STR87##
(wherein, R.sup.3 is a hydrogen atom, a lower alkyl group, an acyl
group, a lower alkylsulfonyl group, a substituted or unsubstituted
phenyl group or a benzyl group), a group represented by formula
##STR88## (wherein, R.sup.4 is a hydrogen atom, a lower alkyl group
or a phenyl group), a group represented by formula ##STR89## a
group represented by formula ##STR90## a group represented by
formula ##STR91## a group represented by formula ##STR92## a group
represented by formula ##STR93## a group represented by formula
##STR94## a group represented by formula ##STR95## (wherein, n is 0
or an integer of 1 to 10, and R.sup.2 is a hydrogen atom or a
methyl group), a group represented by formula
.dbd.(CH--CH.dbd.CH).sub.b-- (wherein, b is an integer of 1 to 3),
a group represented by formula .dbd.CH--(CH.sub.2).sub.c--
(wherein, c is 0 or an integer of 1 to 9), a group represented by
formula .dbd.(CH--CH).sub.d.dbd. (wherein, d is 0 or an integer of
1 to 5), a group represented by formula ##STR96## a group
represented by formula ##STR97## a group represented by formula
##STR98## a group represented by formula ##STR99## a group
represented by formula --NH--, a group represented by formula
--O--, a group represented by formula --S--, a
dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl group, T
is a nitrogen atom or a carbon atom, Q is a nitrogen atom, a carbon
atom or a group represented by formula ##STR100## K is a hydrogen
atom, a substituted or unsubstituted phenyl group, an arylalkyl
group in which a phenyl group may be substituted, a cinnamyl group
in which a phenyl group may be substituted, a lower alkyl group, a
pyridylmethyl group, a cycloalkylalkyl group, an adamantanemethyl
group, a furylmethyl group, a substituted or unsubstituted
cycloalkyl group, a lower alkoxycarbonyl group or an acyl group, q
is an integer of 1 to 3, and indicates a single bond or a double
bond).
3. A method according to claim 2, wherein J is a group selected
from the group consisting of: substituted or unsubstituted (1)
phenyl group, (2) pyridyl group, (3) pyradyl group, (4) quinolyl
group, (5) cyclohexyl group, (6) quinoxalyl group and (7) furyl
group.
4. A method according to claim 2, wherein J is a monovalent group
derived from a cyclic amide compound.
5. A method according to claim 1, wherein a compound having a
cholinesterase inhibitory activity is a cyclic amine derivatives
represented by the following general formula: ##STR101## (wherein,
J.sup.1 is a monovalent or divalent group derived from a group
selected from the group consisting of (1) indanyl, (2) indanonyl,
(3) indenyl, (4) indenonyl, (5) indandionyl, (6) tetralonyl, (7)
benzsuberonyl, (8) indanolyl, and (9) a group represented by
formula ##STR102## in all of which a phenyl group may be
substituted, B is a group represented by formula ##STR103## a group
represented by formula ##STR104## a group represented by formula
##STR105## (wherein, R.sup.3 is a hydrogen atom, a lower alkyl
group, an acyl group, a lower alkylsulfonyl group, a substituted or
unsubstituted phenyl group or a benzyl group), a group represented
by formula ##STR106## (wherein, R.sup.4 is a hydrogen atom, a lower
alkyl group --CH.dbd.CH--(CH).sub.n-- or a phenyl group), a group
represented by formula ##STR107## a group represented by formula
##STR108## a group represented by formula ##STR109## a group
represented by formula ##STR110## a group represented by formula
##STR111## a group represented by formula ##STR112## a group
represented by formula ##STR113## (wherein, n is 0 or an integer of
1 to 10, and R.sup.2 is a hydrogen atom or a methyl group), a group
represented by formula .dbd.(CH--CH.dbd.CH).sub.b-- (wherein, b is
an integer of 1 to 3), a group represented by formula
.dbd.CH--(CH.sub.2).sub.c-- (wherein, c is 0 or an integer of 1 to
9), a group represented by formula .dbd.(CH--CH).sub.d.dbd.
(wherein, d is 0 or an integer of 1 to 5), a group represented by
formula ##STR114## a group represented by formula ##STR115## a
group represented by formula ##STR116## a group represented by
formula ##STR117## a group represented by formula --NH--, a group
represented by formula --O--, a group represented by formula --S--,
a dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl group,
T is a nitrogen atom or a carbon atom, Q is a nitrogen atom, a
carbon atom or a group represented by formula ##STR118## K is a
hydrogen atom, a substituted or unsubstituted phenyl group, an
arylalkyl group in which a phenyl group may be substituted, a
cinnamyl group in which a phenyl group may be substituted, a lower
alkyl group, a pyridylmethyl group, a cycloalkylalkyl group, an
adamantanemethyl group, a furylmethyl group, a substituted or
unsubstituted cycloalkyl group, a lower alkoxycarbonyl group or an
acyl group, q is an integer of 1 to 3, and indicates a single bond
or a double bond).
6. A method according to claim 5, wherein B is a group represented
by formula ##STR119## (wherein n is 0 or an integer of 1 to 10, and
R.sup.2 is a hydrogen atom or a methyl group), a group represented
by formula --CH.dbd.CH--(CH).sub.nR.sup.2-- (wherein, n is 0 or an
integer of 1 to 10, R.sup.2 is a hydrogen atom or a methyl group),
a group represented by formula .dbd.(CH--CH.dbd.CH).sub.b--
(wherein, b is an integer of 1 to 3), a group represented by
formula .dbd.CH--(CH.sub.2).sub.c-- (wherein, c is 0 or an integer
of 1 to 9) or a group represented by formula
.dbd.(CH--CH).sub.d.dbd. (wherein, d is 0 or an integer of 1 to
5).
7. A method according to claim 1, wherein a compound having a
cholinesterase inhibitory activity is a cyclic amine derivative
represented by the following general formula: ##STR120## (wherein,
J.sup.1 is a monovalent or divalent group derived from a group
selected from the group consisting of (1) indanyl, (2) indanonyl,
(3) indenyl, (4) indenonyl, (5) indandionyl, (6) tetralonyl, (7)
benzsuberonyl, (8) indanolyl, (9) a group represented by formula
##STR121## in all of which a phenyl group may be substituted,
B.sup.1 is a group represented by formula ##STR122## (wherein, n is
0 or an integer of 1 to 10, and R.sup.2 is a hydrogen atom or a
methyl group), a group represented by formula
--CH.dbd.CH--(CH).sub.nR.sup.2-- (wherein, n is 0 or an integer of
1 to 10, and R.sup.2 is a hydrogen atom or a methyl group), a group
represented by formula .dbd.(CH--CH.dbd.CH).sub.b-- (wherein, b is
an integer of 1 to 3), a group represented by formula
.dbd.CH--(CH.sub.2).sub.c-- (wherein, c is 0 or an integer of 1 to
9) or a group represented by formula .dbd.(CH--CH).sub.d.dbd.
(wherein, d is 0 or an integer of 1 to 5), and K is a hydrogen
atom, a substituted or unsubstituted phenyl group, an arylalkyl
group in which a phenyl group may be substituted, a cinnamyl group
in which a phenyl group may be substituted, a lower alkyl group, a
pyridylmethyl group, a cycloalkylalkyl group, an adamantanemethyl
group, a furylmethyl group, a substituted or unsubstituted
cycloalkyl group, a lower alkoxycarbonyl group or an acyl
group).
8. A method according to claim 7, wherein K is a substituted or
unsubstituted arylalkyl group or phenyl group.
9. A method according to either one of claims 7 and 8, wherein
J.sup.1 is a group selected from the group consisting of monovalent
and divalent groups derived from indanonyl, indenyl and
indandionyl.
10. A method according to either one of claims 7 and 8, wherein
J.sup.1 is an indanonyl group which may contain, as a substituent,
a lower alkyl group with a carbon number 1 to 6 or a lower alkoxy
group with a carbon number 1 to 6.
11. A method according to claim 2, wherein the cyclic amine
derivative is at least one selected from the group consisting of:
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine,
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-ylidenyl)methylpiperidine,
1-benzyl-4-((5-methoxy-1-indanone)-2-yl)methylpiperidine,
1-benzyl-4-((5,6-methylenedioxy-1-indanone)-2-yl)methylpiperidine,
1-(m-nitrobenzyl)-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine,
1-cyclohexylmethyl-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine,
1-(m-fluorobenzyl)-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine,
1-benzyl-4-(3-((5,6-dimethoxy-1-indanone)-2-yl)propyl)piperidine,
1-benzyl-4-((5-isopropoxy-6-methoxy-1-indanone)-2-yl)methylpiperidine,
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-ylidenyl)propenylpiperidine,
and
1-benzyl-4-((5,6-dimethoxy-1,3-indandione)-2-yl)propenylpiperidine.
12. A method according to claim 2, wherein the cyclic amine
derivative is
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine.
13. A method according to claim 1, wherein the compound having a
cholinesterase inhibitory activity is
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-yl) methylpiperidine
hydrochloride.
14. A method according to claim 1, wherein the compound having a
cholinesterase inhibitory activity is galantamine, tacrine,
physostigmine or rivastigmine.
15. A process for screening a substance for suppressing overactive
bladder resulting from cerebral infarction, comprising:
administering a compound having a cholinesterase inhibitory
activity, a pharmacologically acceptable salt or a solvate thereof
to a non-human mammal; and detecting or determining at least one
selected from the group consisting of a bladder capacity, a bladder
contraction pressure and an amount of retained urine, in the
presence and absence of the compound, the pharmacologically
acceptable salt or the solvate thereof.
16. A method according to claim 15, wherein the compound having a
cholinesterase inhibitory activity is a compound having an
acetylcholinesterase inhibitory activity, a pharmacologically
acceptable salt or a solvate thereof.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to an agent and a method for
treating overactive bladder resulting from cerebral infarction.
BACKGROUND OF THE INVENTION
[0002] Overactive bladder is a disease recently recognized by the
International Continence Society (ICS), whose major symptom being
urinary urgency, which may involve urinary frequency, sometimes
causing urinary incontinence. Drugs that can be used by urologists
at present for treating overactive bladder such as urinary urgency,
urinary frequency and urinary incontinence are limited to
anticholinergic agents (antimuscarinic agents). While
anticholinergic agents suppress bladder contractions via
acetylcholine (ACh), they are also associated with common side
effects such as dry mouth (salivation disorder) and constipation.
This is because a subtype of muscarine receptor (M3) in the bladder
commonly exist in the salivary gland and the gastrointestinal
tract. Therefore, patients with gastrointestinal tract obstruction
(such as ileus) cannot be administered with an anticholinergic
agent.
[0003] Overactive bladders are observed in 50-70% of the patients
with lower urinary tract obstruction such as prostatic hyperplasia,
and administration of anticholinergic agents may worsen their
drainage obstruction. Furthermore, anticholinergic agents are
mentioned of its transfer to the nerve center where it may possibly
damage higher brain functions (recognition, learning, emotion,
memory and sleep). From this viewpoint, drugs that rely on new
mechanism have been expected.
[0004] Overactive bladder is found in many patients suffering from
brain diseases such as cerebral infarction, cerebral hemorrhage and
Parkinson's disease. In addition, it is reported that ischemia in
the brain is associated with deterioration of acetylcholine (ACh)
system functions. So far, we have studied how this deterioration of
the ACh nerve function is related with overactive bladder. As a
result, we came to consider that ACh system that projects to the
cerebral cortex from the forebrain basal ganglia projects
suppressively to the micturition reflex center, and since this
projecting system is antagonized by pirenzepine, i.e., a muscarine
M1 receptor blocking agent, overactive bladder is mediated by
muscarine M1 receptor (Yokoyama O, Ootsuka N, Komatsu K, Kodama K,
Yotsuyanagi S, Niikura S, Nagasaka Y, Nakada Y, Kanie S, Namiki M:
Forebrain muscarinic control of micturition reflex in rats.
Neuropharmocology 41:629-638, 2001). When Aniracetam that
stimulates ACh release in the brain is administered to a rat or
human with overactive bladder caused by cerebrovascular disease,
suppression of micturition reflex is observed (Nakada Y, Yokoyama
O, Kamatsu K, Kodama K, Yotsuyanagi S, Niikura S, Nagasaka Y and
Namiki M: Effects of aniracetam on bladder overactivity in rats
with cerebral infarction. J Pharmacol Exp Ther 293: 921-928, 2000,
and Osamu Yokoyama: Micturition Disorder, From Basic Research to
Clinical Application, Journal of Japanese Urological Association
91: 140, 2000), which suggests that activation of ACh system in the
brain may possibly ameliorate overactive bladder.
[0005] On the other hand, as therapeutic agents for lower urinary
tract disorder, several compounds with acetylcholinesterase
inhibitory activities have been reported. Lower urinary tract
disease can be classified into micturition disorders and urine
collection disorders. As one of the therapeutic agents for the
former disorders, a non-carbamate amine compound with an
acetylcholinesterase inhibitory activity has been reported
(International Patent Publication No. 00/18391 pamphlet). However,
as to the latter case, i.e., urine collection disorders involved in
the overactive bladder such as urinary urgency, urinary frequency
and urinary incontinence, no disclosure or suggestion has been
made.
[0006] Donepezil hydrochloride is a substance that reversibly
inhibits acetylcholinesterase, i.e., an acetylcholine-degrading
enzyme, which increases the amount of acetylcholine in the brain
and activates cholinergic nervous system in the brain. This
substance is extensively used as therapeutic agents for senile
dementia of Alzheimer type and Alzheimer's disease (Japanese Patent
No. 2578475). However, whether this centrally-active
acetylcholinesterase inhibitor, donepezil hydrochloride, has effect
on urine collection disorder associated with overactive bladder
such as urinary urgency, urinary frequency and urinary incontinence
resulting from cerebral infarction has not been confirmed.
SUMMARY OF THE INVENTION
[0007] The present invention provides a drug effective in treating
urine collection disorder associated with overactive bladder having
symptoms such as urinary urgency, urinary frequency and urinary
incontinence.
[0008] As a result of devoting studies on the above-described
problems, we found that when donepezil hydrochloride that inhibits
acetylcholinesterase in the brain and that increases acetylcholine
(ACh) in the brain was administered to rats with cerebral
infarction, micturition reflex was suppressed, i.e., overactive
bladder was ameliorated (Masaharu Nakai et al., Journal of
Neurogenic Bladder Society 14:172, 2003 (Abstracts), and Masaharu
Nakai et al., Journal of Japanese Urological Association 95: 413,
2004 (Abstracts)). This result suggests that donepezil
hydrochloride activates ACh system in the brain and possibly
ameliorates overactive bladder resulting from cerebral infarction.
Based on these findings, we completed the present invention.
[0009] Thus, the present invention provides the followings.
[0010] (1) A method for treating overactive bladder resulting from
cerebral infarction, comprising administrating a compound having a
cholinesterase inhibitory activity, a pharmacologically acceptable
salt or a solvate thereof to a patient with the overactive bladder
resulting from cerebral infarction.
[0011] An example of a compound having a cholinesterase inhibitory
activity used in the method of the present invention includes a
cyclic amine derivatives represented by the following general
formula: ##STR1## (wherein, J is:
[0012] (a) a substituted or unsubstituted (1) phenyl group, (2)
pyridyl group, (3) pyradyl group, (4) quinolyl group, (5)
cyclohexyl group, (6) quinoxalyl group or (7) furyl group;
[0013] (b) a monovalent or divalent group derived from a group
selected from the group consisting of (1) indanyl, (2) indanonyl,
(3) indenyl, (4) indenonyl, (5) indandionyl, (6) tetralonyl, (7)
benzsuberonyl, (8) indanolyl, or (9) a group represented by formula
##STR2## in all of which a phenyl group may be substituted;
[0014] (c) a monovalent group derived from a cyclic amide
compound;
[0015] (d) a lower alkyl group; or
[0016] (e) a group represented by formula R.sup.1--CH.dbd.CH--
(wherein R.sup.1 is a hydrogen atom or a lower alkoxycarbonyl
group),
[0017] B is a group represented by formula ##STR3## a group
represented by formula ##STR4## a group represented by formula
##STR5## (wherein, R.sup.3 is a hydrogen atom, a lower alkyl group,
an acyl group, a lower alkylsulfonyl group, a substituted or
unsubstituted phenyl group or a benzyl group), a group represented
by formula ##STR6## (wherein, R.sup.4 is a hydrogen atom, a lower
alkyl group or a phenyl group), a group represented by formula
##STR7## a group represented by formula ##STR8## a group
represented by formula ##STR9## a group represented by formula
##STR10## a group represented by formula ##STR11## a group
represented by formula ##STR12## a group represented by formula
##STR13## (wherein, n is 0 or an integer of 1 to 10, and R.sup.2 is
a hydrogen atom or a methyl group), a group represented by formula
.dbd.(CH--CH.dbd.CH).sub.b-- (wherein, b is an integer of 1 to 3),
a group represented by formula .dbd.CH--(CH.sub.2).sub.c--
(wherein, c is 0 or an integer of 1 to 9), a group represented by
formula .dbd.(CH--CH).sub.d.dbd. (wherein, d is 0 or an integer of
1 to 5), a group represented by formula ##STR14## a group
represented by formula ##STR15## a group represented by formula
##STR16## a group represented by formula ##STR17## a group
represented by formula --NH--, a group represented by formula
--O--, a group represented by formula --S--, a
dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl
group,
[0018] T is a nitrogen atom or a carbon atom,
[0019] Q is a nitrogen atom, a carbon atom or a group represented
by formula ##STR18##
[0020] K is a hydrogen atom, a substituted or unsubstituted phenyl
group, an arylalkyl group in which a phenyl group may be
substituted, a cinnamyl group in which a phenyl group may be
substituted, a lower alkyl group, a pyridylmethyl group, a
cycloalkylalkyl group, an adamantanemethyl group, a furylmethyl
group, a substituted or unsubstituted cycloalkyl group, a lower
alkoxycarbonyl group or an acyl group,
[0021] q is an integer of 1 to 3, and
[0022] indicates a single bond or a double bond).
[0023] Specifically, said J may be a group selected from the group
consisting of substituted or unsubstituted (1) phenyl group, (2)
pyridyl group, (3) pyradyl group, (4) quinolyl group, (5)
cyclohexyl group, (6) quinoxalyl group and (7) furyl group.
Furthermore, said J may be a monovalent group derived from a cyclic
amide compound.
[0024] The compound having a cholinesterase inhibitory activity
described above may be a cyclic amine derivative represented by the
following general formula: ##STR19## (wherein, J.sup.1 is a
monovalent or divalent group derived from a group selected from the
following group consisting of (1) indanyl, (2) indanonyl, (3)
indenyl, (4) indenonyl, (5) indandionyl, (6) tetralonyl, (7)
benzsuberonyl, (8) indanolyl and (9) a group represented by formula
##STR20## in all of which a phenyl group may be substituted,
[0025] B is a group represented by formula ##STR21## a group
represented by formula ##STR22## a group represented by formula
##STR23## (wherein, R.sup.3 is a hydrogen atom, a lower alkyl
group, an acyl group, a lower alkylsulfonyl group, a substituted or
unsubstituted phenyl group or a benzyl group), a group represented
by formula ##STR24## (wherein, R.sup.4 is a hydrogen atom, a lower
alkyl group a phenyl group), a group represented by formula
##STR25## a group represented by formula ##STR26## a group
represented by formula ##STR27## a group represented by ##STR28## a
group represented by formula ##STR29## a group represented by
formula ##STR30## a group represented by formula ##STR31##
(wherein, n is 0 or an integer of 1 to 10, and R.sup.2 is a
hydrogen atom or a methyl group), a group represented by formula
.dbd.(CH--CH.dbd.CH).sub.b-- (wherein, b is an integer of 1 to 3),
a group represented by formula .dbd.CH--(CH.sub.2).sub.c--
(wherein, c is 0 or an integer of 1 to 9), a group represented by
formula .dbd.(CH--CH).sub.d.dbd. (wherein, d is 0 or an integer of
1 to 5), a group represented by formula ##STR32## a group
represented by formula ##STR33## a group represented by formula
##STR34## a group represented by formula ##STR35## a group
represented by formula --NH--, a group represented by formula
--O--, a group represented by formula --S--, a
dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl
group,
[0026] T is a nitrogen atom or a carbon atom,
[0027] Q is a nitrogen atom, a carbon atom or a group represented
by formula ##STR36##
[0028] K is a hydrogen atom, a substituted or unsubstituted phenyl
group, an arylalkyl group in which a phenyl group may be
substituted, a cinnamyl group in which a phenyl group may be
substituted, a lower alkyl group, a pyridylmethyl group, a
cycloalkylalkyl group, an adamantanemethyl group, a furylmethyl
group, a substituted or unsubstituted cycloalkyl group, a lower
alkoxycarbonyl group or an acyl group,
[0029] q is an integer of 1 to 3, and
[0030] indicates a single bond or a double bond).
[0031] Specifically, B may be a group represented by formula
##STR37## (wherein, n is 0 or an integer of 1 to 10 and R.sup.2 is
a hydrogen atom or a methyl group), a group represented by formula
--CH.dbd.CH--(CH).sub.nR.sup.2-- (wherein, n is 0 or an integer of
1 to 10 and R.sup.2 is a hydrogen atom or a methyl group), a group
represented by formula .dbd.(CH--CH.dbd.CH).sub.b-- (wherein, b is
an integer of 1 to 3), a group represented by formula
.dbd.CH--(CH.sub.2).sub.c-- (wherein, c is 0 or an integer of 1 to
9) or a group represented by formula .dbd.(CH--CH).sub.d.dbd.
(wherein, d is 0 or an integer of 1 to 5).
[0032] Furthermore, the compound having the cholinesterase
inhibitory activity described above may be a cyclic amine
derivative represented by the following general formula: ##STR38##
(wherein, J.sup.1 is a monovalent or divalent group derived from a
group selected from the group consisting of (1) indanyl, (2)
indanonyl, (3) indenyl, (4) indenonyl, (5) indandionyl, (6)
tetralonyl, (7) benzsuberonyl, (8) indanolyl and (9) a group
represented by formula ##STR39## in all of which a phenyl group may
be substituted,
[0033] B.sup.1 is a group represented by formula ##STR40##
(wherein, n is 0 or an integer of 1 to 10, and R.sup.2 is a
hydrogen atom or a methyl group), a group represented by formula
--CH.dbd.CH--(CH).sub.nR.sup.2-- (wherein, n is 0 or an integer of
1 to 10 and R.sup.2 is a hydrogen atom or a methyl group), a group
represented by formula .dbd.(CH--CH.dbd.CH).sub.b-- (wherein, b is
an integer of 1 to 3), a group represented by formula
.dbd.CH--(CH.sub.2).sub.n-- (wherein, c is 0 or an integer of 1 to
9) or a group represented by formula .dbd.(CH--CH).sub.d.dbd.
(wherein, d is 0 or an integer of 1 to 5), and
[0034] K is a hydrogen atom, a substituted or unsubstituted phenyl
group, an arylalkyl group in which a phenyl group may be
substituted, a cinnamyl group in which a phenyl group may be
substituted, a lower alkyl group, a pyridylmethyl group, a
cycloalkylalkyl group, an adamantanemethyl group, a furylmethyl
group, a substituted or unsubstituted cycloalkyl group, a lower
alkoxycarbonyl group or an acyl group).
[0035] Specifically, said K may be a substituted or unsubstituted
arylalkyl group or phenyl group, and said J.sup.1 may be a group
selected from the group consisting of monovalent groups and
divalent groups derived from indanonyl, indenyl and indandionyl.
Furthermore, an example of J.sup.1 includes an indanonyl group
which may have as a substituent a lower alkyl group with a carbon
number 1 to 6 or a lower alkoxy group with a carbon number 1 to
6.
[0036] The above-mentioned cyclic amine derivative may be at least
one selected from the group consisting of:
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine,
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-ylidenyl)methylpiperidine,
1-benzyl-4-((5-methoxy-1-indanone)-2-yl)methylpiperidine,
1-benzyl-4-((5,6-methylenedioxy-1-indanone)-2-yl)methylpiperidine,
1-(m-nitrobenzyl)-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine,
1-cyclohexylmethyl-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine,
1-(m-fluorobenzyl)-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine,
1-benzyl-4-(3-((5,6-dimethoxy-1-indanone)-2-yl)propyl)piperidine,
1-benzyl-4-((5-isopropoxy-6-methoxy-1-indanone)-2-yl)methylpiperidine,
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-ylidenyl)propenylpiperidine,
and
1-benzyl-4-((5,6-dimethoxy-1,3-indandione)-2-yl)propenylpiperidine,
or may be
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine.
According to the present invention, a compound with a
cholinesterase inhibitory activity is preferably
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine
hydrochloride.
[0037] The compound having an acetylcholinesterase inhibitory
activity described above may be galantamine, tacrine, physostigmine
or rivastigmine.
[0038] (2) A process for screening a substance for suppressing
overactive bladder resulting from cerebral infarction, comprising:
administering a candidate substance to a non-human mammal; and
detecting or determining a change in a phenotype of the overactive
bladder resulting from cerebral infarction in the presence and
absence of the candidate substance.
[0039] For the screening process of the present invention, the
candidate substance include, for example, a compound having a
cholinesterase inhibitory activity, a pharmacologically acceptable
salt or a solvate thereof. Herein, the change in the phenotype of
overactive bladder resulting from cerebral infarction can use as an
index at least one selected from the group consisting of a bladder
capacity, a bladder contraction pressure and an amount of retained
urine.
BRIEF DESCRIPTION OF THE DRAWINGS
[0040] FIG. 1 shows changes in cholineacetyltransferase activities
in right and left cortices and right and left hippocampi after
cerebral infarction;
[0041] FIG. 2 shows change in bladder capacities with respect to
doses of intravenously injected donepezil hydrochloride;
[0042] FIG. 3 shows change in bladder capacities with respect to
doses of intraventricularly injected donepezil hydrochloride;
[0043] FIG. 4 shows change in bladder capacities with respect to
doses of donepezil hydrochloride;
[0044] FIG. 5 shows percentage of change in micturition contraction
pressure;
[0045] FIG. 6 shows comparison of cerebral infarct volumes between
a group of infarction rats administered with donepezil
hydrochloride (CI+D group) and a group of cerebral infarction rats
administered with vehicle (CI+Ve group);
[0046] FIG. 7 shows changes in cholineacetyltransferase activities
in right and left cortices and right and left hippocampi after
cerebral infarction;
[0047] FIG. 8 shows cholineacetyltransferase activity in pons after
cerebral infarction;
[0048] FIG. 9 shows change in curves of pressure within bladders of
rats intraventricularly administered with donepezil hydrochloride
and their removed brains;
[0049] FIG. 10 shows change in bladder capacities with respect to
doses of donepezil hydrochloride;
[0050] FIG. 11 shows percentage of change in micturition
contraction pressure;
[0051] FIG. 12 shows change in bladder capacities upon donepezil
hydrochloride administration; and
[0052] FIG. 13 shows percentage of change in micturition
contraction pressure.
DETAILED DESCRIPTION OF THE INVENTION
[0053] 1. Compound with Cholinesterase (ChE) Inhibitory
Activity
[0054] According to the present invention, an active substance for
treating overactive bladder resulting from cerebral infarction
comprises a compound with a ChE inhibitory activity, a
pharmacologically acceptable salt or a solvate thereof. The
compound with a ChE inhibitory activity according to the present
invention refers to a substance with a ChE inhibitory activity,
i.e., a substance that reversibly or irreversibly inhibits a ChE
activity. In the present invention, ChE comprises
acetylcholinesterase (ACHE) (EC3.1.1.7), butyrylcholinesterase or
the like. Preferable features of the compound with a ChE inhibitory
activity of the present invention include that it is highly
selective for ACHE over butyrylcholinesterase, it effects
centrally, it is capable of passing through the blood-brain
barrier, and it does not cause severe side effect at a dose
required for treatment.
[0055] According to the present invention, a preferable compound
used as a therapeutic agent for overactive bladder resulting from
cerebral infarction comprises a compound with a ChE, particularly
ACHE inhibitory activity. This compound comprises a
pharmacologically acceptable salt of the compound with a ChE
inhibitory activity, a solvate thereof and a prodrug thereof as
described below.
[0056] (1) Compound with Cholinesterase Inhibitory Activity
[0057] According to the present invention, compounds with a ChE
inhibitory activity include donepezil (ARICEPT.RTM.), galantamine
(Reminyl.RTM.), tacrine (Cognex.RTM.), rivastigmine (Exelon.RTM.),
zifrosilone (U.S. Pat. No. 5,693,668 specification), physostigmine
(Synapton) (Neurobiology of Aging 26 (2005) 939-946), ipidacrine
(U.S. Pat. No. 4,550,113 specification), quilostigmine, metrifonate
(Promem) (U.S. Pat. No. 4,950,658 specification), eptastigmine,
velnacrine, tolserine, cymserine (U.S. Pat. No. 6,410,747
specification), mestinon, icopezil (U.S. Pat. No. 5,750,542
specification), TAK-147 (J. Med. Chem., 37(15), 2292-2299, 1994,
Japanese Patent Publication No. 2650537, U.S. Pat. No. 5,273,974
specification), huperzine A (Drugs Fut., 24, 647-663, 1999),
stacofylline (U.S. Pat. No. 4,599,338 specification),
thiatolserine, neostigmine, eseroline, or thiacymserine,
8-[3-[1-[(3-fluorophenyl)methyl]-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetr-
ahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one (Japanese Patent
Publication No. 3512786), phenserine or ZT-1. The compound may also
be a derivative or a prodrug of the above compounds. In addition, a
pharmacologically acceptable salt or a solvate of the above
compounds, derivatives and prodrugs may also be included as
preferred embodiments of the compound with a ChE inhibitory
activity. The compound with a ChE inhibitory activity also includes
the compound with a ChE inhibitory activity described in
International Patent Publication No. 00/18391 pamphlet.
[0058] Galantamine and derivatives thereof are described in U.S.
Pat. No. 4,663,318 specification, International Patent Publication
No. 88/08708 pamphlet, International Patent Publication No.
97/03987 pamphlet, U.S. Pat. No. 6,316,439 specification, U.S. Pat.
No. 6,323,195 specification, U.S. Pat. No. 6,323,196 specification
and the like. Tacrine and derivatives thereof are described in U.S.
Pat. No. 4,631,286 specification, U.S. Pat. No. 4,695,573
specification, U.S. Pat. No. 4,754,050 specification, International
Patent Publication No. 88/02256 pamphlet, U.S. Pat. No. 4,835,275
specification, U.S. Pat. No. 4,839,364 specification, U.S. Pat. No.
4,999,430 specification, International Patent Publication
WO97/21681 pamphlet and the like. Physostigmine and derivatives
thereof are described in U.S. Pat. No. 5,077,289 specification,
U.S. Pat. No. 5,177,101 specification, U.S. Pat. No. 5,302,721
specification, Japanese Laid-Open Application No. 5-306286, U.S.
Pat. No. 7,166,824 specification, EP Patent No. 298202
specification, International Patent Publication No. 98/27096
pamphlet, J. Pharm. Exp. Therap., 249 (1), 194-202, 1989 and the
like. Rivastigmine and derivatives thereof are described in EP
Patent No. 193926 specification, International Patent Publication
No. 98/26775 pamphlet, International Patent Publication No.
98/27055 pamphlet and the like.
[0059] "Prodrug" as used herein means a drug obtained by chemically
modifying "an active ingredient of a drug" (i.e., a "drug"
corresponding to the prodrug) into an inactive substance for the
purpose of bioavailability improvement, alleviation of side effects
or the like, which, after absorption, is metabolized to an active
ingredient in the body and exerts action. Thus, the term "prodrug"
refers to any compound that has a lower intrinsic activity than a
corresponding "drug" but which, when administered to a biological
system, generates the "drug" substance as a result of spontaneous
chemical reaction, enzyme catalysis or metabolic reaction. Examples
of such prodrugs include those in which an amino group, a hydroxyl
group or a carboxyl group of the above-exemplified compound or a
compound represented by the general formula below has been
acylated, alkylated, phosphorylated, borated, carbonated,
esterified, amidated or urethanated. This exemplified group,
however, merely represents typical examples and thus is not
comprehensive. Those skilled in the art can prepare other various
known prodrugs from the above-exemplified compound or the compound
represented by the general formula below according to a known
method. A prodrug comprising the above-exemplified compound or the
compound represented by the general formula below is within the
scope of the invention.
[0060] (2) Cyclic Amine Derivatives
[0061] According to the present invention, preferred examples of a
compound with a ChE inhibitory activity, specifically an ACHE
inhibitory activity further include a cyclic amine derivative
represented by the following general formula (I), a
pharmacologically acceptable salt and a solvate thereof. According
to the present invention, a compound with a ChE inhibitory activity
is preferably
1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpiperidine
(donepezil), a pharmacologically acceptable salt or a solvate
thereof, more preferably
1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpiperidine
hydrochloride (donepezil hydrochloride), i.e., ARICEPT.RTM..
[0062] General Formula (I) ##STR41## (wherein, J refers to one
selected from groups (a) to (e) listed below:
[0063] (a) a substituted or unsubstituted (1) phenyl group, (2)
pyridyl group, (3) pyradyl group, (4) quinolyl group, (5)
cyclohexyl group, (6) quinoxalyl group or (7) furyl group;
[0064] (b) a monovalent or divalent group derived from one selected
from the group consisting of (1) indanyl, (2) indanonyl, (3)
indenyl, (4) indenonyl, (5) indandionyl, (6) tetralonyl, (7)
benzsuberonyl, (8) indanolyl, and (9) a group represented by
formula ##STR42## in all of which a phenyl group may be
substituted,
[0065] (c) a monovalent group derived from a cyclic amide
compound,
[0066] (d) a lower alkyl group, or
[0067] (e) a group represented by formula R.sup.1--CH.dbd.CH--
(wherein, R.sup.1 is a hydrogen atom or a lower alkoxycarbonyl
group),
[0068] B refers to a group represented by formula ##STR43## a group
represented by formula ##STR44## a group represented by formula
##STR45## (wherein, R.sup.3 is a hydrogen atom, a lower alkyl
group, an acyl group, a lower alkylsulfonyl group, a substituted or
unsubstituted phenyl group or a benzyl group), a group represented
by formula ##STR46## (wherein, R.sup.4 is a hydrogen atom, a lower
alkyl group or a phenyl group), a group represented by formula
##STR47## a group represented by formula ##STR48## a group
represented by formula ##STR49## a group represented by formula
##STR50## a group represented by formula ##STR51## a group
represented by formula ##STR52## a group represented by formula
##STR53## (wherein, n is 0 or an integer of 1 to 10, and R.sup.2 is
a hydrogen atom or a methyl group), a group represented by formula
.dbd.(CH--CH.dbd.CH).sub.b-- (wherein, b is an integer of 1 to 3),
a group represented by formula .dbd.CH--(CH.sub.2).sub.c--
(wherein, c is 0 or an integer of 1 to 9), a group represented by
formula .dbd.(CH--CH).sub.d.dbd. (wherein, d is 0 or an integer of
1 to 5), a group represented by formula ##STR54## a group
represented by formula ##STR55## a group represented by formula
##STR56## a group represented by formula ##STR57## a group
represented by formula --NH--, a group represented by formula
--O--, a group represented by formula --S--, a
dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl
group,
[0069] T represents a nitrogen atom or a carbon atom,
[0070] Q represents a nitrogen atom, a carbon atom or a group
represented by formula ##STR58##
[0071] K is a hydrogen atom, a substituted or unsubstituted phenyl
group, an arylalkyl group in which a phenyl group may be
substituted, a cinnamyl group in which a phenyl group may be
substituted, a lower alkyl group, a pyridylmethyl group, a
cycloalkylalkyl group, an adamantanemethyl group, a furylmethyl
group, a substituted or unsubstituted cycloalkyl group, a lower
alkoxycarbonyl group or an acyl group,
[0072] q is an integer of 1 to 3, and
[0073] indicates a single bond or a double bond).
[0074] "A lower alkyl group" as used herein comprises a straight or
branched alkyl group with a carbon number 1 to 6, for example, a
methyl group, an ethyl group, an n-propyl group, an isopropyl
group, an n-butyl group, an isobutyl group, a sec-butyl group, a
tert-butyl group, a pentyl group (an amyl group), an isopentyl
group, a neopentyl group, a tert-pentyl group, a 1-methylbutyl
group, a 2-methylbutyl group, a 1,2-dimethylpropyl group, a hexyl
group, an isohexyl group, a 1-methylpentyl group, a 2-methylpentyl
group, a 3-methylpentyl group, a 1,1-dimethylbutyl group, a
1,2-dimethylbutyl group, a 2,2-dimethylbutyl group, a
1,3-dimethylbutyl group, a 2,3-dimethylbutyl group, a
3,3-dimethylbutyl group, a 1-ethylbutyl group, a 2-ethylbutyl
group, a 1,1,2-trimethylpropyl group, a 1,2,2-trimethylpropyl
group, a 1-ethyl-1-methylpropyl group, a 1-ethyl-2-methylpropyl
group and the like. Preferable groups among them include a methyl
group, an ethyl group, a propyl group and an isopropyl group, most
preferable group being a methyl group. "A lower alkyl group" is
described in the definition of the above compound (I) of the
present invention, for example, in the definitions of J, K, R.sup.3
and R.sup.4.
[0075] "A lower alkoxy group" as used herein means a lower alkoxy
group corresponding to the above-mentioned lower alkyl group such
as a methoxy group and an ethoxy group.
[0076] "A lower alkoxycarbonyl group" as used herein means a lower
alkoxycarbonyl group corresponding to the above-mentioned lower
alkoxy group such as a methoxycarbonyl group, an ethoxycarbonyl
group, an isopropoxycarbonyl group, an n-propoxycarbonyl group and
an n-butyloxycarbonyl group.
[0077] "A cycloalkyl group" as used herein refers to a cyclic alkyl
group with a carbon number 4 to 10, including but not limited to a
cyclobutyl group, a cyclopentyl group and a cyclohexyl group.
[0078] "J"
[0079] In the definition of J, exemplary substituents for "(a)
substituted or unsubstituted (1) phenyl group, (2) pyridyl group,
(3) pyradyl group, (4) quinolyl group, (5) cyclohexyl group, (6)
quinoxalyl group or (7) furyl group" include:
[0080] a lower alkyl group with a carbon number 1 to 6 such as a
methyl group, an ethyl group, an n-propyl group, an isopropyl
group, an n-butyl group, an isobutyl group and a tert-butyl
group;
[0081] a lower alkoxy group corresponding to a lower alkyl group
such as a methoxy group and an ethoxy group;
[0082] a nitro group;
[0083] a halogen such as chlorine, bromine and fluorine;
[0084] a carboxyl group;
[0085] a lower alkoxycarbonyl group corresponding to the lower
alkoxy group above such as a methoxycarbonyl group, an
ethoxycarbonyl group, an isopropoxycarbonyl group, an
n-propoxycarbonyl group and an n-butyloxycarbonyl group;
[0086] an amino group;
[0087] a mono-lower alkylamino group;
[0088] a di-lower alkylamino group;
[0089] a carbamoyl group;
[0090] an acylamino group derived from aliphatic saturated
monocarboxylic acid with a carbon number 1 to 6 such as an
acetylamino group, a propionylamino group, a butyrylamino group, an
isobutyrylamino group, a valerylamino group and a pivaloyl amino
group;
[0091] a cycloalkyloxycarbonyl group such as a
cyclohexyloxycarbonyl group;
[0092] a lower alkylaminocarbonyl group such as a
methylaminocarbonyl group and an ethylaminocarbonyl group;
[0093] a lower alkylcarbonyloxy group corresponding to the lower
alkyl group defined above such as a methylcarbonyloxy group, an
ethylcarbonyloxy group and an n-propylcarbonyloxy group;
[0094] a halogenated lower alkyl group as represented by a
trifluoromethyl group or the like;
[0095] a hydroxyl group;
[0096] a formyl group; and
[0097] a lower alkoxy lower alkyl group such as an ethoxymethyl
group, a methoxymethyl group and a methoxyethyl group.
[0098] As to the above substituents, "the lower alkyl group" and
"the lower alkoxy group" comprise all of the groups that can be
derived from the definition described above. Groups (1) to (7) from
(a) may be substituted with 1 to 3 of the same or different
substituents mentioned above.
[0099] In the case of the phenyl group, the following case is also
to be included in the substituted phenyl group: that is, when a
group can be represented by formula ##STR59## (wherein, G is a
group represented by ##STR60## a group represented by ##STR61## a
group represented by --O--, a group represented by ##STR62## a
group represented by --CH.sub.2--O--, a group represented by
--CH.sub.2--SO.sub.2--, a group represented by ##STR63## or a group
represented by ##STR64## and
[0100] E represents a carbon atom or a nitrogen atom).
[0101] D may represent a lower alkyl group with a carbon number 1
to 6 such as a methyl group, an ethyl group, an n-propyl group, an
isopropyl group, an n-butyl group, an isobutyl group, and a
tert-butyl group;
[0102] a lower alkoxy group corresponding to the lower alkyl group
above such as a methoxy group and an ethoxy group;
[0103] a nitro group;
[0104] a halogen such as chlorine, bromine and fluorine;
[0105] a carboxyl group;
[0106] a lower alkoxycarbonyl group corresponding to the lower
alkoxy group above such as a methoxycarbonyl group, an
ethoxycarbonyl group, an isopropoxycarbonyl group, an
n-propoxycarbonyl group and an n-butyloxycarbonyl group;
[0107] an amino group;
[0108] a mono-lower amino group;
[0109] a di-lower alkylamino group;
[0110] a carbamoyl group;
[0111] an acylamino group derived from aliphatic saturated
monocarboxylic acid with a carbon number 1 to 6 such as an
acetylamino group, a propionylamino group, a butyrylamino group, an
isobutyrylamino group, a valerylamino group and a pivaloylamino
group;
[0112] a cycloalkyloxycarbonyl group such as a
cyclohexyloxycarbonyl group;
[0113] a lower alkylaminocarbonyl group such as a
methylaminocarbonyl group and an ethylaminocarbonyl group;
[0114] a lower alkylcarbonyloxy group corresponding to the lower
alkyl group defined above such as a methylcarbonyloxy group, an
ethylcarbonyloxy group and an n-propylcarbonyloxy group;
[0115] a halogenated lower alkyl group as represented by a
trifluoromethyl group;
[0116] a hydroxyl group;
[0117] a formyl group;
[0118] a lower alkoxy lower alkyl group such as an ethoxymethyl
group, a methoxymethyl group and a methoxyethyl group.
[0119] As to the substituents, "the lower alkyl group" and "the
lower alkoxy group" comprise all of the groups that can be derived
from the definition described above.
[0120] Among those mentioned above, substituents favorable for a
phenyl group include a lower alkyl group, a lower alkoxy group, a
nitro group, a halogenated lower alkyl group, a lower
alkoxycarbonyl group, a formyl group, a hydroxyl group, a lower
alkoxy lower alkyl group, a halogen, a benzoyl group and a
benzylsulfonyl group. The substituents may be two or more and may
be the same or different.
[0121] Preferred substituents for a pyridyl group may include a
lower alkyl group, an amino group and a halogen atom.
[0122] Preferred substituents for a pyradyl group may include a
lower alkoxycarbonyl group, a carboxyl group, an acylamino group, a
carbamoyl group and a cycloalkyloxycarbonyl group.
[0123] When representing "J", 2-pyridyl group, 3-pyridyl group or
4-pyridyl group is desirable as a pyridyl group, 2-pyradyl group is
desirable as a pyradyl group, 2-quinolyl group or 3-quinolyl group
is desirable as a quinolyl group, 2-quinoxalyl group or
3-quinoxalyl group is desirable as a quinoxalyl group, and 2-furyl
group is desirable as a furyl group.
[0124] In the definition of "J", typical examples of the monovalent
or divalent group derived from (1) to (9) listed in group (b) are
shown below: ##STR65##
[0125] In the above series of formulae, t means 0 or an integer of
1 to 4, indicating that the phenyl group is substituted by 0 to 4
groups indicated by S which may be the same or different. S
identically or differently indicates one of the substituents listed
in (a) in the definition of J or a hydrogen atom and preferably
includes a hydrogen atom (unsubstituted), a lower alkyl group or a
lower alkoxy group. Furthermore, the phenyl group may be
substituted by an alkylenedioxy group such as a methylenedioxy
group or an ethylenedioxy group between adjacent carbons of the
phenyl ring.
[0126] Among those mentioned above, a preferable case is where no
substitution exist, where 1 to 3 methoxy groups or isopropoxy
groups are substituted, or where a methylenedioxy group is
substituted. Most preferable case is where no substitution exist,
or where 1 to 3 methoxy groups are substituted.
[0127] The above-mentioned indanolydenyl is an example where a
divalent group in which a phenyl group listed in (b) in the
definition of J may be substituted, i.e., a typical divalent group
derived from (2) indanonyl in J (b).
[0128] In the definition of J, examples of the monovalent group
derived from a cyclic amide compound from (c) include, for example,
quinazolone, tetrahydroisoquinoline-one,
tetrahydrobenzodiazepine-one and hexahydrobenzazocin-one, but are
not limited thereto as long as a cyclic amide exists in the
structural formula.
[0129] The cyclic amide may be derived from a monocyclic ring or a
condensed heterocyclic ring. Preferably, the condensed heterocyclic
ring is a condensed heterocyclic ring with a phenyl ring. In this
case, the phenyl ring may be substituted with a lower alkyl group
with a carbon number 1 to 6, preferably a methyl group, a lower
alkoxy group with a carbon number 1 to 6, preferably a methoxy
group or a halogen atom.
[0130] Preferable examples include the following: ##STR66##
##STR67## (wherein, Y in formulae (i) and (l) represents a hydrogen
atom or a lower alkyl group, V in formula (k) represents a hydrogen
atom or a lower alkoxy group, W.sup.1 and W.sup.2 in formulae (m)
and (n) each independently represent, identically or differently, a
hydrogen atom, a lower alkyl group or a lower alkoxy group, and
W.sup.3 is a hydrogen atom or a lower alkyl group. U in formula (j)
represents a hydrogen atom, a lower alkyl group or a lower alkoxy
group.
[0131] The rings on the right side in formulae (j) and (l) are
seven-membered rings, and the ring on the right side in formula (k)
is an eight-membered ring.
[0132] For the definition of J, "(d) a lower alkyl group" is as
described above.
[0133] Among those included in the above definition of J, groups
included in (a) to (c) are preferable, most preferable group being
a monovalent group derived from indanone (indanonyl) included in
(b) where a phenyl ring may be substituted or unsubstituted, and a
monovalent group derived from a cyclic amide compound included in
(c).
[0134] "B"
[0135] For the definition of B, a group represented by formula:
##STR68## is indicated as formula --(CH.sub.2).sub.n-- when R.sup.2
is a hydrogen atom. In this case, any of the carbon atoms of the
alkylene chain may further bind to one or more methyl groups and n
is preferably 1 to 3.
[0136] In B, examples of "dialkylaminoalkylcarbonyl group" include,
for example, N,N-dimethylaminoalkylcarbonyl group,
N,N-diethylaminoalkylcarbonyl group,
N,N-diisopropylaminoalkylcarbonyl group, and
N-methyl-N-ethylaminoalkylcarbonyl group.
[0137] As to a series of groups of B, a group including an amide
group is also preferable.
[0138] Examples of preferable groups further include a group
represented by formula --CH.dbd.CH--(CH).sub.nR.sup.2-- (wherein, n
is 0 or an integer of 1 to 10, and R.sup.2 is a hydrogen atom or a
methyl group), a group represented by formula
.dbd.(CH--CH.dbd.CH).sub.b-- (wherein, b is an integer of 1 to 3),
a group represented by formula .dbd.CH--(CH.sub.2).sub.c--
(wherein, c is 0 or an integer of 1 to 9), a group represented by
formula .dbd.(CH--CH).sub.d.dbd. (wherein, d represents 0 or an
integer of 1 to 5), a group represented by formula --NH--, a group
represented by formula --O-- and a group represented by formula
--S--.
[0139] "T", "Q" and "q"
[0140] A ring ##STR69## may be a five- to seven-membered ring.
Specifically, examples of such ring include ##STR70## although
particularly preferable ring is piperidine represented by formula
##STR71##
[0141] "K" and "Bonds"
[0142] As to expressions "substituted or unsubstituted phenyl
group", "substituted or unsubstituted arylalkyl group (where a
phenyl group may be substituted)", "cinnamyl group where a phenyl
group may be substituted", and "cycloalkyl group which may be
substituted" in the definition of K, the substituents are the same
as those defined in definition of J for (a) (1) to (7). These are
preferably unsubstituted or may be substituted with a nitro group,
a lower alkyl group such as methyl or a halogen such as
fluorine.
[0143] An arylalkyl group is intended to mean a benzyl group or a
phenetyl group in which a phenyl ring is substituted with a
substituent described above or unsubstituted.
[0144] Examples of pyridylmethyl group may specifically include
2-pyridylmethyl group, 3-pyridylmethyl group and 4-pyridylmethyl
group.
[0145] As to K, an arylalkyl group where a phenyl group may be
substituted, a substituted or unsubstituted phenyl group, a
cinnamyl group where a phenyl group may be substituted and a
cycloalkyl group which may be substituted are most preferable.
[0146] Preferable arylalkyl group is specifically, for example, a
benzyl group or a phenetyl group in which a phenyl group may be
substituted with a lower alkoxy group having a carbon number 1 to
6, a lower alkyl group having a carbon number 1 to 6, a hydroxyl
group or the like.
[0147] indicates a single bond or a double bond. An exemplary case
of the double bond includes the above-described divalent group
derived from indanone where a phenyl ring may be substituted,
namely an indanolydenyl group.
[0148] Compound Group (A)
[0149] Gathering from these definitions, particularly preferable
compound group include compound group (A) represented by the
following general formula, i.e., a cyclic amine represented by
formula: ##STR72## (wherein, J.sup.1 is a monovalent or divalent
group derived from a group selected from the group consisting of:
(1) indanyl, (2) indanonyl, (3) indenyl, (4) indenonyl, (5)
indandionyl, (6) tetralonyl, (7) benzsuberonyl, (8) indanolyl, and
(9) a group represented by formula ##STR73## in all of which a
phenyl group may be substituted; and
[0150] B, T, Q, q, K and have the same meaning as described above),
a pharmacologically acceptable salt or a solvate thereof.
[0151] In the above definition of J.sup.1, the most preferable
groups include an indanonyl group, an indandionyl group and
indanolydenyl group where a phenyl group may be substituted.
Specifically, a phenyl group may be unsubstituted or substituted
identically or differently with a hydroxyl group, a halogen or a
lower alkoxy group, and most preferably substituted with an
alkylenedioxy group between adjacent carbon atoms of a phenyl ring.
A lower alkoxy group refers to, for example, a methoxy group, an
ethoxy group, an isopropoxy group, an n-propoxy group and an
n-butoxy group with a carbon number 1 to 6, and can take a form of
mono- to tetra-substitution, preferably disubstitution.
Disubstitution of the methoxy group is most preferable.
[0152] Compound Group (B)
[0153] More preferable compound group included in formula (A)
include a compound group represented by the following general
formula (B): ##STR74## (wherein, J.sup.1 is the same as described
above,
[0154] B.sup.1 is a group represented by ##STR75## (wherein, n is 0
or an integer of 1 to 10, and R.sup.2 is a hydrogen atom or a
methyl group), a group represented by formula
--CH.dbd.CH--(CH)R.sup.2-- (wherein, n represents 0 or an integer
of 1 to 10, and R.sup.2 represents a hydrogen atom or a methyl
group), a group represented by formula .dbd.(CH--CH.dbd.CH).sub.b--
(wherein, b is an integer of 1 to 3), a group represented by
formula .dbd.CH--(CH.sub.2).sub.c-- (wherein, c represents 0 or an
integer of 1 to 9) or a group represented by formula
.dbd.(CH--CH).sub.d.dbd. (wherein, d is 0 or an integer of 1 to 5):
Preferably, B.sup.1 is a group represented by formula
--(CH).sub.nR.sup.2-- (wherein, n is 0 or an integer of 1 to 10,
and R.sup.2 is a hydrogen atom or a methyl group), more preferably
--CH.sub.2-- (wherein, n=1, and R.sup.2 is a hydrogen atom), or
--CH.sub.2--CH.sub.2--CH.sub.2-- (wherein, n=3, and R.sup.2 is a
hydrogen atom): B.sup.1 is preferably a group represented by
formula --CH.dbd.CH--(CH).sub.nR.sup.2-- (wherein, n is 0 or an
integer of 1 to 10, and R.sup.2 is a hydrogen atom or a methyl
group), more preferably --CH.dbd.CH--CH.sub.2-- (wherein, n=1 and
R.sup.2 is a hydrogen atom), and
[0155] T, Q, q, K and are as described above).
[0156] Compound Group (C)
[0157] More preferable compound group included in formula (B) may
include a compound group represented by the following general
formula (C): ##STR76## (wherein, J.sup.1, B.sup.1, K and are as
described above).
[0158] Specifically, the group represented by formula ##STR77## is
indicated by a group represented by formula ##STR78## i.e.,
piperidine.
[0159] Compound Group (D)
[0160] More preferable compound group included in formula (C) may
include a compound group represented by the following general
formula (D): ##STR79## (wherein, J.sup.2 is a group selected from a
monovalent or divalent group derived from indanonyl where a phenyl
group may be substituted (e.g., indanonyl, indanolydenyl group),
indenyl and indandionyl: More preferably, J.sup.2 is an indanonyl
group which may have, as a substituent, a lower alkyl group with a
carbon number 1 to 6 or a lower alkoxy group with a carbon number 1
to 6,
[0161] K.sup.1 is a substituted or unsubstituted phenyl group, an
arylalkyl group which may be substituted, a cinnamyl group which
may be substituted or a cycloalkyl group which may be substituted,
and
B.sup.1 and are as described above).
[0162] Moreover, a particularly preferable compound group (a
compound group having a ChE inhibitory activity) of cyclic amine
derivatives represented by general formula (I) or pharmacologically
acceptable salts thereof includes the following: [0163]
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine,
[0164]
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-ylidenyl)methylpiperidine,
[0165] 1-benzyl-4-((5-methoxy-1-indanone)-2-yl)methylpiperidine,
[0166]
1-benzyl-4-((5,6-methylenedioxy-1-indanone)-2-yl)methylpiperidine,
[0167]
1-(m-nitrobenzyl)-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperi-
dine, [0168]
1-cyclohexylmethyl-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine,
[0169]
1-(m-fluorobenzyl)-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiper-
idine, [0170]
1-benzyl-4-(3-((5,6-dimethoxy-1-indanone)-2-yl)propyl)piperidine,
[0171]
1-benzyl-4-((5-isopropoxy-6-methoxy-1-indanone)-2-yl)methylpiperidine,
[0172]
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-ylidenyl)propenyl)piperi-
dine, and [0173]
1-benzyl-4-((5,6-dimethoxy-1,3-indandione)-2-yl)propenylpiperidine,
[0174] more preferably
1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine.
[0175] (3) Production Process
[0176] A compound having a ChE inhibitory activity, a
pharmacologically acceptable salt thereof or a solvate thereof used
in the present invention can be produced according to a known
method. The cyclic amine derivatives represented by the general
formula (I) above (e.g., donepezil hydrochloride) can readily be
produced by methods disclosed, as representative examples, in
Japanese Laid-Open Application No. 1-79151, Japanese Patent
Publication No. 2578475, Japanese Patent Publication No. 2733203,
Japanese Patent Publication No. 3078244 or U.S. Pat. No. 4,895,841.
Donepezil hydrochloride is also available as a formulation such as
fine granules.
[0177] Galantamine and derivatives thereof can readily be produced
by methods disclosed, for example, in U.S. Pat. No. 4,663,318
specification, International Patent Publication No. 88/08708
pamphlet, International Patent Publication No. 97/03987 pamphlet,
U.S. Pat. No. 6,316,439 specification, U.S. Pat. No. 6,323,195
specification and U.S. Pat. No. 6,323,196 specification.
[0178] Tacrine and derivatives thereof can readily be produced by
methods disclosed, for example, in U.S. Pat. No. 4,631,286
specification, U.S. Pat. No. 4,695,573 specification, U.S. Pat. No.
4,754,050 specification, International Patent Publication No.
88/02256 pamphlet, U.S. Pat. No. 4,835,275 specification, U.S. Pat.
No. 4,839,364 specification, U.S. Pat. No. 4,999,430 specification,
and International Patent Publication WO97/21681 pamphlet.
[0179] Physostigmine and derivatives thereof can readily be
produced by methods disclosed, for example, in U.S. Pat. No.
5,077,289 specification, U.S. Pat. No. 5,177,101 specification,
U.S. Pat. No. 5,302,721 specification, Japanese Laid-Open
Application No. 5-306286, U.S. Pat. No. 7,166,824 specification, EP
Patent No. 298202 specification, International Patent Publication
No. 98/27096 pamphlet, and J. Pharm. Exp. Therap., 249 (1),
194-202, 1989.
[0180] Rivastigmine and derivatives thereof can readily be produced
by methods disclosed, for example, in EP Patent No. 193926
specification, International Patent Publication No. 98/26775
pamphlet, and International Patent Publication No. 98/27055
pamphlet.
[0181] Among these compounds, those that are commercially available
can readily be obtained from, for example, chemical
manufacturers.
[0182] According to the present invention, examples of
pharmacologically acceptable salts include, for example, inorganic
acid salts such as hydrochloride, sulfate, hydrobromate and
phosphate, or organic acid salts such as formate, acetate,
trifluoroacetate, maleate, tartrate, methanesulfonate,
benzenesulfonate and toluenesulfonate.
[0183] In addition, depending on the choice of the substituent, for
example, alkali metal salts such as sodium salt and potassium salt,
alkaline earth metal salts such as calcium salt and magnesium salt,
organic amine salts such as trimethylamine salt, triethylamine
salt, pyridine salt, picoline salt, dicyclohexylamine salt and
N,N'-dibenzylethylenediamine salt, and ammonium salt are
formed.
[0184] According to the present invention, a compound having a ChE
inhibitory activity or a pharmacologically acceptable salt thereof
(e.g., donepezil hydrochloride) as an active ingredient for
overactive bladder treatment may be an anhydride, and may form a
solvate such as a hydrate. According to the present invention, a
solvate is preferably a pharmacologically acceptable solvate. A
pharmacologically acceptable solvate may be either a hydrate or a
nonhydrate, but preferably a hydrate. A solvent such as water,
alcohol (e.g., methanol, ethanol, n-propanol), dimethylformamide,
dimethyl sulfoxide (DMSO) or the like may be used. For example,
crystal polymorph may exist in the above-mentioned donepezil,
although not limited thereto and any form of crystal may exist
alone or in combination.
[0185] According to the present invention, the above-mentioned
compound may have an asymmetric carbon depending on the type of
substituent and may have an enantiomer, which are within the scope
of the present invention.
[0186] In one specific example, if J has an indanone skeleton
associated with an asymmetric carbon, a geometric isomer, an
enantiomer, a diastereomer or the like may exist. All of these
cases are within the scope of the present invention.
[0187] 2. Therapeutic Agent for Overactive Bladder Resulting from
Cerebral Infarction
[0188] According to the present invention, a therapeutic agent for
overactive bladder resulting from cerebral infarction refers to a
drug that increases a bladder capacity that has decreased because
of cerebral infarction in human or organisms other than human such
as non-human mammals including cow, monkey, avian, cat, mouse, rat,
guinea pig, hamster, pig, dog and rabbit. The therapeutic agent of
the present invention activates Ch nervous system in the brain by
inhibiting cholinesterase (ChE) (including acetylcholinesterase
(AChE)) to ameliorate overactive bladder such as urinary urgency,
urinary frequency and urinary incontinence. This means that the
therapeutic agent of the present invention is effective in
ameliorating deterioration of overactive bladder and bladder
capacity caused by deterioration of functions resulting from
cerebral infarction such as deterioration of cholinergic neural
action, preferably deterioration of central cholinergic neural
action, or deterioration of action of choline acetyltransferase,
i.e., ACh-synthesis enzyme, in the central nerve. Thus, the
therapeutic agent of the present invention may effectively be used
for treating overactive bladder in a patient whose cholinergic
neural action has deteriorated because of cerebral infarction, for
example, patients with brain disease such as cerebral infarction
(e.g., lacunar infarction, atherothrombosis or cardiogenic cerebral
infarction), asymptomatic cerebral infarction and cerebral
hemorrhage. The therapeutic agent of the present invention
desirably has no influence on micturition contraction pressure, and
is not associated with urge of urination. Also, the therapeutic
agent of the present invention may be termed either as a
therapeutic agent or an improving agent for urinary urgency,
urinary frequency, urinary incontinence and the like resulting from
cerebral infarction.
[0189] The compound having a ChE inhibitory activity described
above, a pharmacologically acceptable salt or a solvate thereof
increases the bladder capacity. In addition, they are useful as an
active ingredient of a therapeutic agent of the present
invention.
[0190] Thus, the present invention also provides a method for
treating overactive bladder resulting from cerebral infarction,
comprising administering an effective amount of the compound having
a ChE inhibitory activity described above, a pharmacologically
acceptable salt or a solvate thereof to a patient.
[0191] The term "treatment" generally means an achievement of a
desirable pharmacological effect and/or physiological effect. These
effects can be prophylactic in terms of completely or partially
preventing a disease and/or symptoms, and therapeutic in terms of
partially or completely curing a disease and/or adverse effects
caused by a disease. Herein, "treatment" refers to any treatment
for a disease of a mammal, particularly human, and also includes
general treatment as described above. "Treatment" includes, for
example, the following (a) to (c):
[0192] (a) to prevent a disease or a symptom in a patient who is
predisposed to the disease or the symptom but not yet diagnosed to
be so;
[0193] (b) to inhibit a disease or a symptom, that is, to stop or
delay the progress thereof;
[0194] (c) to alleviate a disease or a symptom, that is, to delay
or eliminate the disease or the symptom, or to reverse the progress
of the symptom.
[0195] A compound with a ChE inhibitory activity, a salt or a
solvate thereof, or a prodrug thereof, a salt or a solvate thereof
may be administered either orally or parenterally to a human or
non-human mammal (e.g., intravenous injection, muscle injection,
subcutaneous injection, rectal administration, transdermal
administration) by any one of various means. A compound having a
ChE inhibitory activity, a salt or a solvate thereof, or a prodrug
thereof, a salt or a solvate thereof may be used alone or may be
formulated into an appropriate formulation using a pharmaceutical
carrier by employing a conventionally used method depending on the
administration route.
[0196] Examples of preferable formulations include, for example,
oral formulations such as tablets, powder, fine granules, granules,
coated tablets, capsules, syrup and lozenge, and parenteral
formulations such as inhalers, suppositories, injectable agents
(including intravenous fluids), ointments, ophthalmic drops,
ophthalmic ointments, nasal drops, ear drops, adhesive patches,
skin pads, lotion and liposome formulations.
[0197] Examples of carriers that can be used for formulating these
formulations include, for example, a generally used solvent,
excipient, coating agent, binder, disintegrating agent, lubricant,
colorant, flavoring or aromatic substance, and if necessary, a
stabilizer, an emulsifying agent, an absorption promoter, a
surfactant, a pH regulator, an antiseptics, an antioxidant, a
filler, a wetting agent, a surface-active agent, a dispersant, a
buffer, a preservative, a solubilizing agent, a suspending agent, a
thickening agent, a soothing agent and a tonicity agent, which can
be formulated according to a common procedure by blending materials
generally used for formulating a medicinal formulation. Examples of
such non-toxic materials available include, for example, animal and
vegetable oils such as soybean oil, beef tallow and synthetic
glyceride; for example, hydrocarbons such as liquid paraffin,
squalane and solid paraffin; for example, ester oils such as
octyldodecyl myristate and isopropyl myristate; for example, higher
alcohols such as cetostearyl alcohol and behenyl alcohol; silicon
resin; silicon oil; for example, surfactants such as
polyoxyethylene fatty acid ester, sorbitan fatty acid ester,
glycerine fatty acid ester, polyoxyethylene sorbitan fatty acid
ester, polyoxyethylene hardened caster oil and
polyoxyethylene-polyoxypropylene block copolymer; for example,
water-soluble polymers such as hydroxyethylcellulose, polyacrylic
acid, carboxy vinyl polymer, polyethylene glycol, polyvinyl
pyrrolidone and methylcellulose; for example, lower alcohols such
as ethanol and isopropanol; for example, polyol such as glycerine,
propylene glycol, dipropylene glycol, sorbitol and polyethylene
glycol; for example, saccharides such as glucose and sucrose; for
example, inorganic powers such as anhydrous silicon, magnesium
aluminum silicate and aluminum silicate; inorganic salts such as
sodium chloride and sodium phosphate; and purified water.
[0198] Examples of excipients include, for example, lactose,
fructose, cornstarch, white sugar, glucose, mannitol, sorbit,
crystalline cellulose and silicon dioxide; examples of binders
include, for example, polyvinyl alcohol, polyvinyl ether,
methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin,
shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose,
polyvinyl pyrrolidone, polypropyleneglycol polyoxyethylene block
copolymer and meglumine; examples of disintegrating agents include,
for example, starch, agar, gelatin powder, crystalline cellulose,
calcium carbonate, sodium hydrogen carbonate, calcium citrate,
dextrin, pectin and calcium carboxymethylcellulose; examples of
lubricants include, for example, magnesium stearate, talc,
polyethylene glycol, silica and hardened plant oil; examples of
colorants include pharmaceutically acceptable additives; and
examples of flavoring or aromatic substances include cocoa powder,
menthol, aromatic powder, mint oil, borneol and cinnamon powder.
The materials mentioned above may be salts or solvates thereof.
[0199] An oral formulation is produced, for example, into powder,
fine granule, granule, a tablet, a coated tablet, a capsule or the
like obtained according to a routine procedure after adding an
excipient, and if necessary, further a binder, a disintegrating
agent, a lubricant, a colorant, a flavoring or aromatic substance
or the like to a compound having a ChE inhibitory activity, a salt
or a solvate thereof, or a prodrug thereof, a salt or a solvate
thereof.
[0200] Tablets and granules may be coated according to a well-known
method using a coating agent such as carnauba wax,
hydroxypropylmethylcellulose, macrogol, hydroxypropylmethyl
phthalate, cellulose acetate phthalate, white sugar, titanium
oxide, sorbitan fatty acid ester or calcium phosphate.
[0201] Specific examples of carrier used for producing a syrup
agent include sweetening agents such as white sugar, glucose and
fructose, suspending agents such as gum arabic, tragacanth,
carmellose sodium, methylcellulose, sodium alginate, crystalline
cellulose and veegum, and dispersants such as sorbitan fatty acid
ester, sodium lauryl sulphate and polysorbate 80. For production of
syrup, a flavoring material, an aromatic material, a preservative,
a solubilizing agent and a stabilizer can be added as may be
necessary. The product may be in a form of dry syrup that can be
dissolved or suspended upon use.
[0202] An injectable agent is generally prepared by dissolving, for
example, a salt of a compound having a ChE inhibitory activity in
injectable distilled water, and may be formulated according to a
common procedure by adding a solubilizing agent, a buffer, a pH
regulator, a tonicity agent, a soothing agent, an antiseptic, a
preservative, a stabilizer or the like as may be necessary.
[0203] The injectable agent may be asepticized by filter
sterilization using a filter or by addition of a disinfectant. The
injectable agent may be produced into a form that can be prepared
upon use. Specifically, the injectable agent may be prepared into a
sterile solid composition by lyophilization or the like which can
be dissolved in sterile injectable distilled water or other solvent
before use.
[0204] Production of an external medicine is not limited to a
particular production procedure and may be produced by any routine
procedure. Various materials generally used in pharmaceuticals,
medicated cosmetics, cosmetics or the like may be used as a base
material. For example, materials such as animal or plant oil,
mineral oil, ester oil, wax, higher alcohols, fatty acids, silicon
oil, surfactant, phospholipids, alcohols, polyols, water-soluble
polymers, clay minerals, purified water or the like, and if
necessary, a pH regulator, an antioxidant, a chelating agent, an
antiseptic, a fungicide, a colorant, an aromatic substance or the
like may also be added. As to an inhaler, a compound having a ChE
inhibitory activity, a salt or a solvent thereof, or a prodrug
thereof or a salt or a solvent thereof can be delivered with an
injector, a nebulizer, a pressurized package or other means
suitable for delivering aerosol spray for inhalation
administration. The pressurized package may contain an appropriate
propellant. Moreover, for inhalation administration, a compound
having a ChE inhibitory activity, a salt or a solvate thereof, or a
prodrug thereof, a salt or a solvate thereof may be administered in
a form of dry powdered composition or liquid spray. For
administration with an adhesive patch via transdermal absorption,
it is preferable to select a so-called free-form that does not form
salt. For topical application to skin, a compound having a ChE
inhibitory activity may be formulated into ointment, cream or
lotion or as an active ingredient in a transdermal patch. Ointment
and cream can be formulated, for example, by adding an appropriate
thickening agent and/or gelling agent to an aqueous or oil base.
Lotion can be formulated by using an aqueous or oil base and may
generally contain one or more of an emulsifying agent, a
stabilizer, a dispersant, a suspending agent, a thickening agent
and/or a colorant. The compound having a ChE inhibitory activity
may also be administered by ion transfer therapy.
[0205] If necessary, components such as a blood circulating agent,
a disinfectant, an anti-inflammatory agent, a cellular stimulant,
vitamins, amino acids, a moisturizing agent, a keratolytic agent
may further be blended. The proportion of the active ingredient to
the carrier varies between 1 to 90% by weight.
[0206] The overactive bladder therapeutic agent used in the method
of the present invention can generally include, as an active
ingredient, a compound having a ChE inhibitory activity, a salt or
a solvate thereof, or a prodrug thereof, a salt or a solvate
thereof at a proportion of 0.5% by weight or more, preferably 10 to
70% by weight.
[0207] When the compound having a ChE inhibitory activity, a salt
or a solvate thereof, or a prodrug thereof, a salt or a solvate
thereof is used for the treatment described above, it is purified
for at least 90% or more, preferably 95% or more, more preferably
98% or more, still more preferably 99% or more.
[0208] A dose of the compound having a ChE inhibitory activity, a
salt or a solvate thereof, or a prodrug thereof, a salt or a
solvate thereof for oral administration varies as it is determined
according to multiple factors including, for example,
administration route, type of disease, degree of symptom, patient's
age, sex and weight, type of salt, specific type of disease,
pharmacological aspects such as pharmacokinetics and toxicological
features, use of drug delivery system, and whether it is
administered concomitantly with other drugs, but one skilled in the
art will be able to determine appropriately. For example, for an
adult (60 kg), about 0.001 to 1000 mg/day, preferably about 0.01 to
500 mg/day, and more preferably about 0.1 to 300 mg/day can be
administered at one time or in several times. When administered to
a child, a dose is possibly lower than that for an adult. The
administration procedure actually used may widely vary and can
depart from the preferable administration procedures described
herein. For example, in the case of donepezil hydrochloride,
preferably about 0.1 to 300 mg/day, more preferably about 0.1 to
100 mg/day, and still more preferably about 1.0 to 50 mg/day can be
administered to an adult (weight 60 kg). In a preferred embodiment
of donepezil hydrochloride, a 5 mg or 10 mg donepezil hydrochloride
tablet commercially available under the trade name of Aricept
tablet (Eisai Co., Ltd.), or donepezil hydrochloride under the
trade name of Aricept fine granule (Eisai Co., Ltd.) can be
administered. For example, tablets may be administered 1 to about 4
times a day. In a preferred embodiment, a 5 mg or 10 mg Aricept
tablet (Eisai Co., Ltd.) is administered once a day. Those skilled
in the art will appreciate that when donepezil hydrochloride is
administered to a child, the dose thereof is possibly lower than
that for an adult. In a preferred embodiment, donepezil
hydrochloride can be administered to a child for about 0.5 to 10
mg/day, preferably about 1.0 to 3 mg/day. Preferably, in the case
of Tacrine, about 0.1 to 300 mg/day, preferably about 40 to 120
mg/day is administered to an adult (weight 60 kg); in the case of
Rivastigmine, about 0.1 to 300 mg/day, preferably about 3 to 12
mg/day is administered to an adult (weight 60 kg); in the case of
galantamine, about 0.1 to 300 mg/day, preferably about 16 to 32
mg/day is administered to an adult (weight 60 kg); and in the case
of physostigmine, about 0.1 to 300 mg/day, preferably about 0.6 to
24 mg/day is administered to an adult (weight 60 kg). For each of
the above cases, a dose to a child may possibly be lower than that
for an adult.
[0209] As to parenteral administration, a preferable dose for
adhesive patch would be about 5 to 50 mg/day, more preferably about
10 to 20 mg/day for an adult (60 kg). An injectable agent may be
produced by dissolving or suspending it in a pharmacologically
acceptable carrier such as saline or a commercially available
injectable distilled water to a concentration of 0.1 .mu.g/ml
carrier to 10 mg/ml carrier. A dose of such an injectable agent to
a patient in need of the treatment may be about 0.01 to 50 mg/day,
preferably about 0.01 to 5.0 mg/day, more preferably about 0.1 to
1.0 mg/day for an adult (60 kg), and may be administered 1 to 3
times a day. When administered to a child, the dose may possibly be
lower than that for an adult.
[0210] 3. Process for Screening Substance for Suppressing
Overactive Bladder Resulting from Cerebral Infarction,
Pharmacologically Acceptable Salt or Solvate Thereof.
[0211] The present invention further provides a process for
screening a substance that suppresses overactive bladder resulting
from cerebral infarction, a pharmacologically acceptable salt or a
solvate thereof.
[0212] A screening process according to the present invention
comprises administrating a candidate substance to a non-human
mammal, and detecting or determining a change in a phenotype of
overactive bladder resulting from cerebral infarction in the
presence and absence of the candidate substance.
[0213] Herein, "in the presence" means that the candidate substance
has been administered to a non-human animal, and "in the absence"
means that the candidate substance has not been administered to a
non-human animal. Thus, upon screening, individuals from a
non-human animal group administered with the candidate substance
are compared with individuals from a control non-human animal group
not administered with the candidate substance to detect or
determine the phenotypes. Alternatively, a phenotype of an
individual prior to administration of a candidate substance may be
compared with a phenotype of the same individual administered with
the candidate substance.
[0214] According to the screening process of the present invention,
the candidate substance include a substance having an ChE
(including ACHE) inhibitory activity, for example, the compound
having a ChE inhibitory activity described above, an anti-ChE
antibody, siRNA and shRNA to ChE and the like. The substance may be
a salt or a solvate of the above. The compound having a ChE
inhibitory activity can be produced or obtained by referring to the
description above. The anti-ChE antibody may be either a monoclonal
antibody or a polyclonal antibody, and those skilled in the art
would be able to produce such antibodies, for example, by using ChE
as a sensitized antigen. siRNA or shRNA for ChE gene may be any
nucleic acid that is capable of suppressing the expression of ChE
gene, and those skilled in the art would be able to appropriately
design a sequence and produce siRNA or shRNA (Elbashir, S. M., et.
al., Genes Dev., 15, 188-200, 2001).
[0215] A candidate compound may be administered to a non-human
mammal either orally or parenterally.
[0216] A change in a phenotype of overactive bladder resulting from
cerebral infarction may use at least one of a bladder capacity, a
bladder contraction pressure and an amount of retained urine as an
index. The substance can be determined to be suppressive to
overactive bladder resulting from cerebral infarction when at least
one of the following (a) to (c) applies:
[0217] (a) when the substance increases bladder capacity,
[0218] (b) when the substance prevents bladder contraction pressure
from decreasing, or
[0219] (c) when the substance prevents retained urine from
increasing.
[0220] In order to detect or determine the change in a phenotype of
the overactive bladder resulting from cerebral infarction, a
pressure within the bladder is determined, preferably a pressure
within the non-human mammal bladder in a waking state is
determined.
[0221] The present invention further provides a kit for screening a
substance capable of suppressing overactive bladder resulting from
cerebral infarction, a pharmacologically acceptable salt or a
solvate thereof which are to be used in the method described above.
The screening kit of the invention includes means required for
determining a change in a phenotype of overactive bladder resulting
from cerebral infarction. Agents suitably used upon determining the
phenotype change are general anesthetics (e.g., halothane) and
saline. The screening kit of the present invention may further
include an instruction, a tube, a flask or the like.
EXAMPLES
[0222] Hereinafter, the present invention will be described more
specifically by way of non-limiting examples.
Example 1
Production of Donepezil Hydrochloride
(a) Synthesis of 1-benzyl-4-piperidine carboaldehyde
[0223] ##STR80##
[0224] 26.0 g of methoxymethylenetriphenylphosphonium chloride was
suspended in 200 ml anhydrous ether, and 1.6 M n-butyllithiumhexane
solution was added dropwise at room temperature. After stirring at
room temperature for 30 minutes, the resultant was cooled to
0.degree. C., and 14.35 g 1-benzyl-4-piperidone in 30 ml anhydrous
ether solution was added. After stirring at room temperature for 3
hours, insoluble matter was filtered out and the filtrate was
concentrated under reduced pressure. The obtained residue was
dissolved in ether and extracted with 1N hydrochloric acid.
Following adjustment of pH to 12 with sodium hydroxide solution,
the resultant was extracted with methylene chloride. The resultant
was dried with magnesium sulfate, and concentrated under reduced
pressure. The obtained residue was purified through a silica gel
column, thereby obtaining 5.50 g of oily substance (yield 33%).
[0225] Subsequently, the obtained oily substance was dissolved in
40 ml methanol, and added with 40 ml 1N hydrochloric acid. The
reaction solution was heated to reflux for 3 hours, then
concentrated under reduced pressure. The residue was dissolved in
water. Thereafter, pH of the dissolved solution was adjusted to 12
with sodium hydroxide solution, and extracted with methylene
chloride. The extracted solution was washed with saturated saline,
dried with magnesium sulfate, and concentrated under reduced
pressure. The obtained residue was purified through a silica gel
column to obtain 2.77 g of 1-benzyl-4-piperidinecarboaldehyde
(yield 54%) as an oily substance.
[0226] The structure of the obtained compound was determined by
NMR.
[0227] Molecular formula; C.sub.13H.sub.17NO .sup.1H-NMR (CDC
l.sub.3).delta.; 1.40-2.40 (7H, m), 2.78 (2H, dt), 3.45 (2H, s),
7.20 (5H, s), 9.51 (1H, d).
(b) Synthesis of
1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidenyl]methylpiperidine.hydroc-
hloride (formula below)
[0228] ##STR81##
[0229] This reaction took place in argon atmosphere.
[0230] 2.05 ml diisopropylamine was added to 10 ml anhydrous THF
and 9.12 ml 1.6M n-butyllithium hexane solution was further added
at 0.degree. C. The resultant was stirred at 0.degree. C. for 10
minutes, cooled to -78.degree. C., and added with 2.55 g
5,6-dimethoxy-1-indanone in 30 ml anhydrous THF solution and 2.31
ml hexamethyl phosphoramide. The resultant was stirred at
-78.degree. C. for 15 minutes, added with 2.70 g
1-benzyl-4-piperidinecarboaldehyde obtained in (a) in 30 ml
anhydrous THF solution, and gradually heated to room temperature.
Again stirring at room temperature for another 2 hours, 1% ammonium
chloride solution was added to separate the organic layer. Next,
the aqueous layer was extracted with ethyl acetate, combined with
the organic layer separated above, and washed with saturated
saline. The solution was dried with magnesium sulfate, concentrated
under reduced pressure, and the obtained residue was purified
through a silica gel column (methylene chloride:methanol=500:1 to
100:1). After concentrating the eluate under reduced pressure, the
resultant was dissolved in methylene chloride, added with 10%
hydrochloric acid-ethyl acetate solution, and further concentrated
under reduced pressure to obtain a crystal. This was recrystallized
from methylene chloride-IPE to obtain 3.40 g of
1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidenyl]methylpiperidine
hydrochloride (yield 62%) having the following properties:
[0231] Melting point (.degree. C.); 237-238 (dec.)
[0232] Elementary analysis; as C.sub.24H.sub.27NO.sub.3 HCl, CHN
calculated (%): 69.64 6.82 3.38, found (%): 69.51 6.78 3.30.
(c) 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpiperidine
hydrochloride
[0233] ##STR82##
[0234] 0.40 g of
1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidenyl]methylpiperidine
obtained in (b) was dissolved in 16 ml THF, and 0.04 g of 10%
palladium-carbon was added. After hydrogenating under atmospheric
pressure at room temperature for 6 hours, catalyst was filtered
out, and the filtrate was concentrated under reduced pressure. The
residue was purified through a silica gel column (methylene
chloride:methanol=50:1), and the eluate was concentrated under
reduced pressure. Thereafter, the residue was dissolved in
methylene chloride, added with 10% hydrochloric acid-ethyl acetate
solution, and was further concentrated under reduced pressure,
thereby obtaining a crystal. This was recrystallized from
ethanol-IPE to obtain 0.36 g of
1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpiperidine
hydrochloride (donepezil hydrochloride) (yield 82%) having the
following properties:
[0235] Melting point (.degree. C.); 211-212 (dec.)
[0236] Elementary analysis; as C.sub.24H.sub.29NO.sub.3 HCl, CHN
calculated (%): 69.30 7.27 3.37, found (%): 69.33 7.15 3.22.
Example 2
Cerebral Infarction Model
[0237] 10-week-old female SD rats (purchased from Sankyo Labo
Service Co.) were subjected to cystostomy under anesthesia of 1.5%
halothane. They were further subjected to cervical incision, and a
nylon suture was inserted into their left internal carotid to
produce cerebral infarction by middle cerebral artery embolization.
These cerebral infarction rats were restrained in Bollman cages in
waking state. Measurement of the pressures within their bladders
indicated significant decrease in the bladder capacities (Yokoyama
O, Yoshiyama M, Namiki M, de Groat W C: Influence of anesthesia on
bladder hyperactivity induced by middle cerebral artery occlusion
in the rat. Am J Physiol 273: R1900-R1907, 1997). On the other
hand, decrease in bladder capacity was not seen in sham-operation
rats which were just subjected to common carotid decortication. In
the examples below, experiments were conducted using overactive
bladder model of this cerebral infarction model.
Experiments Using Cerebral Infarction Models:
Cholineacetyltransferase Activity
[0238] The rats were sacrificed 1, 5 and 24 hours after producing
the left middle cerebral artery embolization as described above.
Right and left cortices, right and left hippocampi and pons were
separated immediately to determine cholineacetyltransferase
activity at each site.
[0239] Results are shown in FIG. 1. The left panel in FIG. 1 shows
the results of left (Lt) and right (Rt) cortices, while the right
panel in FIG. 1 shows the results of left (Lt) and right (Rt)
hippocampi. The vertical axis represents the
cholineacetyltransferase activity (nmol/mg wet weight) while the
horizontal axis represents time (hour) after infarction. As a
result, cholineacetyltransferase activity was decreased 24 hours
after the cerebral infarction on the infarction side, i.e., in the
left cortex (Lt. cortex) and the left hippocampus (Lt. hippocampus)
(FIG. 1).
Example 3
Experiments Using Cerebral Infarction Models: Intravenous
Administration of Donepezil Hydrochloride
[0240] Donepezil hydrochloride (ARICEPT.RTM. supplied from Eisai
Co., Ltd.) was dissolved in saline, which was intravenously
administered to overactive bladder model rats at 5.times.10.sup.-7
mg/kg to 5.times.10.sup.-1 mg/kg every 30 minutes. Bladder
capacities of rats administered with various concentrations of
donepezil hydrochloride were determined.
[0241] Results are shown in FIG. 2. In FIG. 2, changes in the
bladder capacities upon administration of donepezil hydrochloride
("+D") or vehicle ("+Ve") at respective concentrations are shown as
percentages of change from that of a control. The left panel shows
the results for cerebral infarction model rats (CI group) while the
right panel shows the results for sham-operation rats (SO group).
As a result, transvenous administration of donepezil hydrochloride
to the cerebral infarction model rats (CI group) increased the
bladder capacities (FIG. 2). Donepezil hydrochloride doses of
5.times.10.sup.-4 mg/kg and 5.times.10.sup.-5 mg/kg showed
significant difference from the vehicle administration group. In
particular, the dose of 5.times.10.sup.-5 mg/kg showed an increase
of 52.8% (p=0.0163). On the other hand, increase of 27.3% was
observed in the sham-operation rats (SO group) upon donepezil
hydrochloride administration, but difference from the vehicle
administration group was not significant. In addition, no change in
the micturition contraction pressure and little retained urine were
observed at the donepezil hydrochloride doses of 5.times.10.sup.-4
mg/kg and 5.times.10.sup.-5 mg/kg.
Example 4
Experiments Using Cerebral Infarction Models: Intraventricular
Administration of Donepezil Hydrochloride
[0242] After producing cerebral infarction rats, drug infusion
tubes were placed in the lateral ventricles of the rats. After the
rats came out from under anesthesia, 5 .mu.l of donepezil
hydrochloride at concentrations of 5.times.10.sup.-7 mg/ml to
5.times.10.sup.-4 mg/ml were intraventricularly administered to
them to examine the effects on the bladder functions.
[0243] Results are shown in FIG. 3. As a result, bladder capacities
increased upon intraventricular administration of donepezil
hydrochloride in both cerebral infarction rats and sham-operation
rats. Specifically, when 5 .mu.l of donepezil hydrochloride at
5.times.10.sup.-5 mg/ml and 5.times.10.sup.-6 mg/ml were
administered to the cerebral infarction rats, bladder capacity
increased with a significant margin from the vehicle administration
group. At an administration of 5.times.10.sup.-5 mg/ml, the
increase was 95.8% (p=0.0088). No change was seen in the
micturition contraction pressure.
Example 5
[0244] In this example, a cholinesterase inhibitor is administered
to rats with overactive bladder resulting from cerebral infarction
to examine change in their bladder functions.
[0245] Recently, ischemia caused in the brain is reported to be
associated with deterioration of functions of acetylcholine system
in the brain. Therefore, activation of ACh system in the brain is
suggested to recover higher brain functions and further ameliorate
overactive bladder such as bladder irritation.
[0246] Thus, in this example, cerebral infarction rats are
experimentally produced and donepezil hydrochloride, i.e., a
central cholinesterase inhibitor used as a treatment drug for
dementia of the Alzheimer type, is administered to them at
different doses so as to examine its effects on the bladder
functions.
[0247] Materials and Methods
[0248] 10-week-old female SD rats were subjected to cystostomy
under anesthesia of 1.5% halothane. After waking, they were
restrained in Bollman cages and pressures within their bladders
were measured. Then, again under halothane anesthesia, a 4-0 nylon
suture was inserted into left middle cerebral artery through common
carotid to produce cerebral infarction rats (these rats are
referred to as "CI"). On the other hand, those with only
decortication of common carotid were produced as a sham-operation
group (these rats are referred to as "SO").
[0249] Donepezil hydrochloride was dissolved in saline and
intravenously administered at 5.times.10.sup.-7 mg/kg to
5.times.10.sup.-1-mg/kg every 30 minutes from an hour after the
operation. Similarly, a group of rats subjected to cerebral
infarction and sham-operation, and administered with saline was
produced as well, as a vehicle.
[0250] Donepezil hydrochloride is indicated as D while vehicle
administered with saline is indicated as Ve. In the four groups
CI+D, CI+Ve, SO+D and SO+Ve, 5 examples per group, i.e., total of
20 examples were produced to determine change in their bladder
capacities and micturation contraction pressures. Mann-Whitney's U
test was employed.
[0251] In addition, functions of ACh system in each site of the
brain after cerebral infarction were assessed. Cerebral infarction
was produced in 10-week-old female SD rats, which were sacrificed
1, 5 and 24 hours after the infarction to determine
cholineacetyltransferase activities in each site of the brain, the
right and left cortices, the right and left hippocampi and the stem
area.
[0252] Results are shown in FIG. 4. FIG. 4 shows change in the
bladder capacity after the cerebral infarction. In the CI group,
bladder capacity gradually increased after the administration of
donepezil hydrochloride, and the bladder capacity most increased at
5.times.10.sup.-4 to 5.times.10.sup.-5 mg/kg. The percentage of
change was 52.8%, and difference from vehicle was significant.
[0253] In the SO group, bladder capacity increased by donepezil
administration but gradually decreased after administration at
5.times.10.sup.-4 mg/kg.
[0254] The change in the micturition contraction pressure is shown
in FIG. 5. Referring to FIG. 5, in both of the CI group and the SO
group, no significant difference is seen between the donepezil
hydrochloride administration group and the vehicle administration
group at 5.times.10.sup.-7 to 5.times.10.sup.-2 mg/kg and the
contraction pressure significantly increased at 5.times.10.sup.-1
mg/kg in the group administered with donepezil.
[0255] Subsequently, difference of cerebral infarction areas
between the donepezil administration group and the saline
administration group in the CI group were compared. Brains were
removed after 6 hours following cerebral infarction. Thereafter,
brains were cut out into coronal sections at 2 mm intervals, which
were stained with 2% TTC (2,3,5-triphenyl-tetrazolium chloride)
solution to determine the cerebral infarction areas.
[0256] Results are shown in FIG. 6. FIG. 6 shows percentage of a
volume of cerebral infarct to that of the entire brain. No
significant difference was seen between the two groups.
[0257] Subsequently, cholineacetyltransferase activities in the
right and left cortices and right and left hippocampi were compared
at 1, 5 and 24 hours after cerebral infarction.
[0258] Results are shown in FIG. 7. As can be appreciated from FIG.
7, cholineacetyltransferase activity was significantly decreased in
the right and left cortices (left panel) as well as in the left
hippocampi (right panel) after 24 hours than after 1 hour.
[0259] The cholineacetyltransferase activity was also examined in
the pons but no significant difference was seen between 1 hour and
24 hours (FIG. 8).
Example 6
[0260] Example 5 showed that donepezil hydrochloride ameliorated
overactive bladder caused after cerebral infarction and that
acetylcholine in the brain was decreased by cerebral infarction.
Therefore, in this example, donepezil hydrochloride was
intraventriculary administered to confirm whether the overactive
bladder was actually ameliorated with donepezil hydrochloride that
activates acetylcholine decrease caused by cerebral infarction.
[0261] Cerebral infarction rats were produced in the same manner as
Example 5 to examine the effect of intraventricularly administered
donepezil hydrochloride on the bladder functions.
[0262] The process was conducted in the same manner as Example 5
except that metal tubes were inserted into lateral ventricles upon
producing cerebral infarction rats. Pressure within the bladder was
measured at the moment of waking, and 2 hours later donepezil
hydrochloride was intraventricularly administered via the tubes
placed. Feasibility of intraventricular administration was
determined after injecting ink into the brain, sacrificing the rats
and removing the brains to verify on their faces. Concentrations of
donepezil hydrochloride were 5.times.10.sup.-7 mg/ml to
5.times.10.sup.-4 mg/ml. As vehicle, saline was infused for 5
.mu.ml. Experiments of five examples for each concentration were
conducted.
[0263] Results are shown in FIGS. 9 and 10. FIG. 9 shows one
exemplary curve of pressure within the bladder intraventricularly
administered with donepezil hydrochloride (concentration for
administration: 5.times.10.sup.-5 mg/ml). As shown in FIG. 10, the
bladder capacity notably increased after the administration of
donepezil hydrochloride. The right panel in FIG. 9 shows brains
removed after sacrifice. The site of cerebral infarction was not
stained with TCC solution while ink was infused in the
ventricle.
[0264] As to the pressure within the bladder, the bladder capacity
was most increased at an administration of 5.times.10.sup.-5 mg/ml
in the cerebral infarction group, and difference from the vehicle
group was significant at 5.times.10.sup.-5 mg/ml and
5.times.10.sup.-6 mg/ml (p=0.0088) (FIG. 10, left panel). In the
sham-operation group, comparison with the vehicle group at a
concentration of 5.times.10.sup.-5 mg/ml that most increased the
bladder capacity showed a tendency for the bladder capacity to
increase in the donepezil group (p=0.93) (FIG. 10, right
panel).
[0265] As to the change in the micturition contraction pressure, no
significant difference was seen between donepezil hydrochloride and
vehicle at respective doses (FIG. 11).
Example 7
[0266] In Example 6, increase in the bladder capacity was also seen
for intraventricular administration confirming again that donepezil
hydrochloride is selective to brain. In this example, in order to
confirm that donepezil hydrochloride acts superior to pons, brain
was removed after cerebral infarction and donepezil hydrochloride
was administered.
[0267] Similar to Examples 5 and 6, following cystostomy, rats were
classified into cerebral infarction group and sham-operation group,
pressures within the bladders were measured, brains were removed
and 5.times.10.sup.-5 mg/ml of donepezil hydrochloride or vehicle
was transvenously administered.
[0268] Results are shown in FIGS. 12 and 13.
[0269] As a result of the pressure measurements within the
bladders, bladder capacity increased after removal of the brains
from rats in the cerebral infarction group, and no increase was
observed upon the subsequent donepezil hydrochloride administration
(FIG. 12, left panel). In the sham-operation group, bladder
capacity decreased upon brain removal but did not change with
donepezil hydrochloride (FIG. 12, right panel). Retained urine was
not observed in any of the cases.
[0270] As to change in the micturation contraction pressure, little
change was observed for both donepezil hydrochloride and vehicle
administrations showing no significant difference (FIG. 13).
[0271] Thus, the examples above show that donepezil hydrochloride
that activates ACh system selectively to brain activates
preferentially over pons and thus ameliorates overactive bladder
caused by cerebral infarction.
INDUSTRIAL APPLICABILITY
[0272] The present invention provides a therapeutic agent for
overactive bladder resulting from cerebral infarction comprising,
as an active ingredient, a compound having a cholinesterase (ChE)
inhibitory activity or a pharmacologically acceptable salt thereof.
An overactive bladder therapeutic agent of the invention is useful
as a novel therapeutic agent for urine collection disorder
associated with overactive bladder resulting from cerebral
infarction. The compound of the invention, for example, donepezil
hydrochloride, has no side effects such as dry mouth, constipation
and urinary excretion disorder which accompany the existing
overactive bladder therapeutic agents. In addition, considering
that most of the patients to be administered are elderly, donepezil
hydrochloride can be administered safely without being concerned
about damage in higher brain functions, and thus can be a
innovative therapeutic agent for overactive bladder resulting from
cerebral infarction.
* * * * *